ContactBiomedical Research Center
251 Bayview Boulevard
Baltimore, MD 21224
Ph.D. - 1992, Psychology, Uniformed Services University of the Health Sciences, Bethesda, Maryland
M.A. - 1988, Psychology, Hebrew University, Jerusalem, Israel
B.S. - 1986, Biology & Psychology, Hebrew University, Jerusalem, Israel
We study neurobiological mechanisms of relapse to drug seeking and choice of drug versus non-drug rewards using rat models developed in the lab (Shaham group). We also study neurophysiological mechanisms of addictive drugs and motivated behavior (Kiyatkin group).
Current projects of Shaham group:
- Relapse to fentanyl seeking after palatable food choice-induced voluntary abstinence
- Relapse to oxycodone seeking after abstinence induced by adverse consequences of drug taking
- Context-induced relapse to heroin seeking
- Choice of remifentanil versus social reward in an operant model
Current projects of Kiyatkin group (In-vivo electrophysiology unit):
- Neurochemical mechanisms of opioid actions in the CNS
- Interactions of opioids with therapeutic drugs and other drugs of abuse
- Electrochemical evaluation of changes in brain oxygen and glucose
Selected recent empirical papers
Venniro, Marco; Zhang, Michelle; Caprioli, Daniele; Hoots, Jennifer K; Golden, Sam A; Heins, Conor; Morales, Marisela; Epstein, David H; Shaham, Yavin
In: Nat Neurosci, vol. 21, no. 11, pp. 1520–1529, 2018, ISSN: 1546-1726 (Electronic); 1097-6256 (Linking).
Addiction treatment has not been appreciably improved by neuroscientific research. One problem is that mechanistic studies using rodent models do not incorporate volitional social factors, which play a critical role in human addiction. Here, using rats, we introduce an operant model of choice between drugs and social interaction. Independent of sex, drug class, drug dose, training conditions, abstinence duration, social housing, or addiction score in Diagnostic & Statistical Manual IV-based and intermittent access models, operant social reward prevented drug self-administration. This protection was lessened by delay or punishment of the social reward but neither measure was correlated with the addiction score. Social-choice-induced abstinence also prevented incubation of methamphetamine craving. This protective effect was associated with activation of central amygdala PKCdelta-expressing inhibitory neurons and inhibition of anterior insular cortex activity. These findings highlight the need for incorporating social factors into neuroscience-based addiction research and support the wider implantation of socially based addiction treatments.
Venniro, Marco; Russell, Trinity I; Ramsey, Leslie A; Richie, Christopher T; Lesscher, Heidi M B; Giovanetti, Simone M; Messing, Robert O; Shaham, Yavin
In: Proc Natl Acad Sci U S A, 2019, ISSN: 1091-6490 (Electronic); 0027-8424 (Linking).
We recently reported that social choice-induced voluntary abstinence prevents incubation of methamphetamine craving in rats. This inhibitory effect was associated with activation of protein kinase-Cdelta (PKCdelta)-expressing neurons in central amygdala lateral division (CeL). In contrast, incubation of craving after forced abstinence was associated with activation of CeL-expressing somatostatin (SOM) neurons. Here we determined the causal role of CeL PKCdelta and SOM in incubation using short-hairpin RNAs against PKCdelta or SOM that we developed and validated. We injected two groups with shPKCdelta or shCtrlPKCdelta into CeL and trained them to lever press for social interaction (6 d) and then for methamphetamine infusions (12 d). We injected two other groups with shSOM or shCtrlSOM into CeL and trained them to lever press for methamphetamine infusions (12 d). We then assessed relapse to methamphetamine seeking after 1 and 15 abstinence days. Between tests, the rats underwent either social choice-induced abstinence (shPKCdelta groups) or homecage forced abstinence (shSOM groups). After test day 15, we assessed PKCdelta and SOM, Fos, and double-labeled expression in CeL and central amygdala medial division (CeM). shPKCdelta CeL injections decreased Fos in CeL PKCdelta-expressing neurons, increased Fos in CeM output neurons, and reversed the inhibitory effect of social choice-induced abstinence on incubated drug seeking on day 15. In contrast, shSOM CeL injections decreased Fos in CeL SOM-expressing neurons, decreased Fos in CeM output neurons, and decreased incubated drug seeking after 15 forced abstinence days. Our results identify dissociable central amygdala mechanisms of abstinence-dependent expression or inhibition of incubation of craving.
Fredriksson, Ida; Applebey, Sarah V; Minier-Toribio, Angelica; Shekara, Aniruddha; Bossert, Jennifer M; Shaham, Yavin
In: Neuropsychopharmacology, vol. 45, no. 5, pp. 770–779, 2020, ISSN: 1740-634X.
In the classical incubation of drug craving rat model, drug seeking is assessed after homecage forced abstinence. However, human abstinence is often voluntary because negative consequences of drug seeking outweigh the desire for the drug. Here, we developed a rat model of incubation of opioid craving after electric barrier-induced voluntary abstinence and determined whether the dopamine stabilizer (-)-OSU6162 would decrease this new form of incubation. We trained male and female rats to self-administer oxycodone (0.1 mg/kg/infusion, 6 h/day) for 14 days. We then exposed them to either homecage forced abstinence or voluntary abstinence induced by an electric barrier of increasing intensity near the drug-paired lever. On abstinence days 1, 15, or 30, we tested the rats for oxycodone seeking without shock and drug. We also examined the effect of (-)-OSU6162 (7.5 and 15 mg/kg) on oxycodone seeking on abstinence day 1 or after 15 days of either voluntary or forced abstinence. Independent of sex, the time-dependent increase in oxycodone seeking after cessation of opioid self-administration (incubation of opioid craving) was stronger after voluntary abstinence than after forced abstinence. In males, (-)-OSU6162 decreased incubated (day 15) but not non-incubated (day 1) oxycodone seeking after either voluntary or forced abstinence. In females, (-)-OSU6162 modestly decreased incubated oxycodone seeking after voluntary but not forced abstinence. Results suggest that voluntary abstinence induced by negative consequences of drug seeking can paradoxically potentiate opioid craving and relapse. We propose the dopamine stabilizer (-)-OSU6162 may serve as an adjunct pharmacological treatment to prevent relapse in male opioid users.
Reiner, David J; Lofaro, Olivia M; Applebey, Sarah V; Korah, Hannah; Venniro, Marco; Cifani, Carlo; Bossert, Jennifer M; Shaham, Yavin
In: J Neurosci, vol. 40, no. 12, pp. 2485–2497, 2020, ISSN: 1529-2401.
We recently developed a rat model of relapse to drug seeking after food choice-induced voluntary abstinence. Here, we used this model to study the role of the orbitofrontal cortex (OFC) and its afferent projections in relapse to fentanyl seeking. We trained male and female rats to self-administer palatable food pellets for 6 d (6 h/d) and intravenous fentanyl (2.5 μg/kg/infusion) for 12 d (6 h/d). We assessed relapse to fentanyl seeking after 13-14 voluntary abstinence days, achieved through a discrete choice procedure between fentanyl infusions and palatable food (20 trials/d). In both sexes, relapse after food choice-induced abstinence was associated with increased expression of the activity marker Fos in the OFC. Pharmacological inactivation of the OFC with muscimol plus baclofen (50 + 50 ng/side) decreased relapse to fentanyl seeking. We then determined projection-specific activation of OFC afferents during the relapse test by using Fos plus the retrograde tracer cholera toxin B (injected into the OFC). Relapse to fentanyl seeking was associated with increased Fos expression in the piriform cortex (Pir) neurons projecting to the OFC, but not in projections from the basolateral amygdala and thalamus. Pharmacological inactivation of the Pir with muscimol plus baclofen decreased relapse to fentanyl seeking after voluntary abstinence. Next, we used an anatomical disconnection procedure to determine whether projections between the Pir and OFC are critical for relapse to fentanyl seeking. Unilateral muscimol plus baclofen injections into the Pir in one hemisphere plus unilateral muscimol plus baclofen injections into the OFC in the contralateral, but not ipsilateral, hemisphere decreased relapse. Our results identify Pir-OFC projections as a new motivation-related pathway critical to relapse to opioid seeking after voluntary abstinence. There are few preclinical studies of fentanyl relapse, and these studies have used experimenter-imposed extinction or forced abstinence procedures. In humans, however, abstinence is often voluntary, with drug available in the drug environment but forgone in favor of nondrug alternative reinforcers. We recently developed a rat model of drug relapse after palatable food choice-induced voluntary abstinence. Here, we used classical pharmacology, immunohistochemistry, and retrograde tracing to demonstrate a critical role of the piriform and orbitofrontal cortices in relapse to opioid seeking after voluntary abstinence.
Bossert, Jennifer M; Kiyatkin, Eugene A; Korah, Hannah; Hoots, Jennifer K; Afzal, Anum; Perekopskiy, David; Thomas, Shruthi; Fredriksson, Ida; Blough, Bruce E; Negus, S Stevens; Epstein, David H; Shaham, Yavin
In a Rat Model of Opioid Maintenance, the G Protein-Biased Mu Opioid Receptor Agonist TRV130 Decreases Relapse to Oxycodone Seeking and Taking and Prevents Oxycodone-Induced Brain Hypoxia Journal Article
In: Biol Psychiatry, vol. 88, no. 12, pp. 935–944, 2020, ISSN: 1873-2402.
BACKGROUND: Maintenance treatment with opioid agonists (buprenorphine, methadone) is effective for opioid addiction but does not eliminate opioid use in all patients. We modeled maintenance treatment in rats that self-administered the prescription opioid oxycodone. The maintenance medication was either buprenorphine or the G protein-biased mu opioid receptor agonist TRV130. We then tested prevention of oxycodone seeking and taking during abstinence using a modified context-induced reinstatement procedure, a rat relapse model.
METHODS: We trained rats to self-administer oxycodone (6 hours/day, 14 days) in context A; infusions were paired with discrete tone-light cues. We then implanted osmotic pumps containing buprenorphine or TRV130 (0, 3, 6, or 9 mg/kg/day) and performed 3 consecutive tests: lever pressing reinforced by oxycodone-associated discrete cues in nondrug context B (extinction responding), context-induced reinstatement of oxycodone seeking in context A, and reacquisition of oxycodone self-administration in context A. We also tested whether TRV130 maintenance would protect against acute oxycodone-induced decreases in nucleus accumbens oxygen levels.
RESULTS: In male rats, buprenorphine and TRV130 decreased extinction responding and reacquisition of oxycodone self-administration but had a weaker (nonsignificant) effect on context-induced reinstatement. In female rats, buprenorphine decreased responding in all 3 tests, while TRV130 decreased only extinction responding. In both sexes, TRV130 prevented acute brain hypoxia induced by moderate doses of oxycodone.
CONCLUSIONS: TRV130 decreased oxycodone seeking and taking during abstinence in a partly sex-specific manner and prevented acute oxycodone-induced brain hypoxia. We propose that G protein-biased mu opioid receptor agonists, currently in development as analgesics, should be considered as relapse prevention maintenance treatment for opioid addiction.
Bossert, Jennifer M; Townsend, E Andrew; Altidor, Lindsay; Fredriksson, Ida; Shekara, Aniruddha; Husbands, Stephen; Sulima, Agnieszka; Rice, Kenner C; Banks, Matthew L; Shaham, Yavin
In: Br J Pharmacol, 2021, ISSN: 1476-5381.
BACKGROUND AND PURPOSE: Maintenance treatment with opioid agonists (buprenorphine, methadone) decreases opioid use and relapse. We recently modeled maintenance treatment in rats and found that chronic delivery of buprenorphine or the mu opioid receptor (MOR) partial agonist TRV130 decreases relapse to oxycodone seeking and taking. Here, we tested the effect of the buprenorphine analog BU08028 on different heroin relapse-related measures and heroin vs. food choice.
EXPERIMENTAL APPROACH: For relapse assessment, we trained male and female rats to self-administer heroin (6-h/d, 14-d) in context A and then implanted osmotic minipumps containing BU08028 (0, 0.03, or 0.1 mg/kg/d). We then tested the effect of chronic BU08028 delivery on (1) incubation of heroin seeking in a non-drug context B, (2) extinction responding reinforced by heroin-associated discrete cues in context B, (3) reinstatement of heroin seeking induced by reexposure to context A, and (4) reacquisition of heroin self-administration in context A. For choice assessment, we tested the effect of chronic BU08028 delivery on heroin vs. food choice.
RESULTS: Chronic BU08028 delivery decreased incubation of heroin seeking. Unexpectedly, BU08028 increased reacquisition of heroin self-administration selectively in females. Chronic BU08028 had minimal effects on context-induced reinstatement and heroin vs. food choice in both sexes. Finally, exploratory post-hoc analyses suggest that BU08028 decreased extinction responding selectively in males.
CONCLUSIONS AND IMPLICATIONS: Chronic BU08028 delivery had both beneficial and detrimental sex-dependent effects on different triggers of heroin relapse and minimal effects on heroin choice in both sexes. Results suggest that BU08028 will not be an effective opioid maintenance treatment in humans.
Fredriksson, Ida; Tsai, Pei-Jung; Shekara, Aniruddha; Duan, Ying; Applebey, Sarah V; Lu, Hanbing; Bossert, Jennifer M; Shaham, Yavin; Yang, Yihong
In: Proc Natl Acad Sci U S A, vol. 118, no. 43, 2021, ISSN: 1091-6490.
We recently introduced a rat model of incubation of opioid craving after voluntary abstinence induced by negative consequences of drug seeking. Here, we used resting-state functional MRI to determine whether longitudinal functional connectivity changes in orbitofrontal cortex (OFC) circuits predict incubation of opioid craving after voluntary abstinence. We trained rats to self-administer for 14 d either intravenous oxycodone or palatable food. After 3 d, we introduced an electric barrier for 12 d that caused cessation of reward self-administration. We tested the rats for oxycodone or food seeking under extinction conditions immediately after self-administration training (early abstinence) and after electric barrier exposure (late abstinence). We imaged their brains before self-administration and during early and late abstinence. We analyzed changes in OFC functional connectivity induced by reward self-administration and electric barrier-induced abstinence. Oxycodone seeking was greater during late than early abstinence (incubation of oxycodone craving). Oxycodone self-administration experience increased OFC functional connectivity with dorsal striatum and related circuits that was positively correlated with incubated oxycodone seeking. In contrast, electric barrier-induced abstinence decreased OFC functional connectivity with dorsal striatum and related circuits that was negatively correlated with incubated oxycodone seeking. Food seeking was greater during early than late abstinence (abatement of food craving). Food self-administration experience and electric barrier-induced abstinence decreased or maintained functional connectivity in these circuits that were not correlated with abated food seeking. Opposing functional connectivity changes in OFC with dorsal striatum and related circuits induced by opioid self-administration versus voluntary abstinence predicted individual differences in incubation of opioid craving.
Selected recent reviews
Reiner, David J; Fredriksson, Ida; Lofaro, Olivia M; Bossert, Jennifer M; Shaham, Yavin
In: Neuropsychopharmacology, 2018, ISSN: 1740-634X (Electronic); 0893-133X (Linking).
Lifetime relapse rates remain a major obstacle in addressing the current opioid crisis. Relapse to opioid use can be modeled in rodent studies where drug self-administration is followed by a period of abstinence and a subsequent test for drug seeking. Abstinence can be achieved through extinction training, forced abstinence, or voluntary abstinence. Voluntary abstinence can be accomplished by introducing adverse consequences of continued drug self-administration (e.g., punishment or electric barrier) or by introducing an alternative nondrug reward in a discrete choice procedure (drug versus palatable food or social interaction). In this review, we first discuss pharmacological and circuit mechanisms of opioid seeking, as assessed in the classical extinction-reinstatement model, where reinstatement is induced by reexposure to the self-administered drug (drug priming), discrete cues, discriminative cues, drug-associated contexts, different forms of stress, or withdrawal states. Next, we discuss pharmacological and circuit mechanisms of relapse after forced or voluntary abstinence, including the phenomenon of "incubation of heroin craving" (the time-dependent increases in heroin seeking during abstinence). We conclude by discussing the clinical implications of these preclinical relapse models.
Venniro, Marco; Banks, Matthew L; Heilig, Markus; Epstein, David H; Shaham, Yavin
In: Nature Reviews Neuroscience, 2020, ISBN: 1471-0048.
Critical features of human addiction are increasingly being incorporated into complementary animal models, including escalation of drug intake, punished drug seeking and taking, intermittent drug access, choice between drug and non-drug rewards, and assessment of individual differences based on criteria in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Combined with new technologies, these models advanced our understanding of brain mechanisms of drug self-administration and relapse, but these mechanistic gains have not led to improvements in addiction treatment. This problem is not unique to addiction neuroscience, but it is an increasing source of disappointment and calls to regroup. Here we first summarize behavioural and neurobiological results from the animal models mentioned above. We then propose a reverse translational approach, whose goal is to develop models that mimic successful treatments: opioid agonist maintenance, contingency management and the community-reinforcement approach. These reverse-translated `treatments'may provide an ecologically relevant platform from which to discover new circuits, test new medications and improve translation.
Fredriksson, Ida; Venniro, Marco; Reiner, David J; Chow, Jonathan J; Bossert, Jennifer M; Shaham, Yavin
In: Pharmacological Reviews, vol. 73, no. 3, pp. 1050–1083, 2021, ISSN: 0031-6997.
Relapse to drug use during abstinence is a defining feature of addiction. During the last several decades, this clinical scenario has been studied at the preclinical level using classic relapse/reinstatement models in which drug seeking is assessed after experimenter-imposed home-cage forced abstinence or extinction of the drug-reinforced responding in the self-administration chambers. To date, however, results from studies using rat relapse/reinstatement models have yet to result in Food and Drug Administration–approved medications for relapse prevention. The reasons for this state of affairs are complex and multifaceted, but one potential reason is that, in humans, abstinence is often self-imposed or voluntary and occurs either because the negative consequences of drug use outweigh the drugtextquoterights rewarding effects or because of the availability of nondrug alternative rewards that are chosen over the drug. Based on these considerations, we and others have recently developed rat models of relapse after voluntary abstinence, achieved either by introducing adverse consequences to drug taking (punishment) or seeking (electric barrier) or by providing mutually exclusive choices between the self-administered drug and nondrug rewards (palatable food or social interaction). In this review, we provide an overview of these translationally relevant relapse models and discuss recent neuropharmacological findings from studies using these models. We also discuss sex as a biological variable, future directions, and clinical implications of results from relapse studies using voluntary abstinence models. Our main conclusion is that the neuropharmacological mechanisms controlling relapse to drug seeking after voluntary abstinence are often different from the mechanisms controlling relapse after home-cage forced abstinence or reinstatement after extinction.Significance Statement This review describes recently developed rat models of relapse after voluntary abstinence, achieved either by introducing adverse consequences to drug taking or seeking or by providing mutually exclusive choices between the self-administered drug and nondrug rewards. This review discusses recent neuropharmacological findings from studies using these models and discusses future directions and clinical implications.
Kiyatkin, Eugene A
In: Neuropharmacology, vol. 151, pp. 219–226, 2019, ISSN: 1873-7064.
Opioid drugs are important tools to alleviate pain of different origins, but they have strong addictive potential and their abuse at higher doses often results in serious health complications. Respiratory depression that leads to brain hypoxia is perhaps the most dangerous symptom of acute intoxication with opioids, and it could result in lethality. The development of substrate-specific sensors coupled with amperometry made it possible to directly evaluate physiological and drug-induced fluctuations in brain oxygen levels in awake, freely-moving rats. The goal of this review paper is to consider changes in brain oxygen levels induced by several opioid drugs (heroin, fentanyl, oxycodone, morphine). While some of these drugs are widely used in clinical practice, they all are abused, often at doses exceeding the clinical range and often resulting in serious health complications. First, we consider some basic knowledge regarding brain oxygen, its physiological fluctuations, and mechanisms involved in regulating its entry into brain tissue. Then, we present and discuss data on brain oxygen changes induced by each opioid drug within a wide range of doses, from low, behaviorally relevant, to high, likely to be self-administered by drug users. These data allowed us to compare the effects of these drugs on brain oxygen in terms of their potency, time-course, and their potential danger when used at high doses via rapid-onset administration routes. While most data discussed in this work were obtained in rats, we believe that these data have clear human relevance in addressing the alarming rise in lethality associated with the opioid abuse.
Perekopskiy, David; Afzal, Anum; Jackson, Shelley N; Muller, Ludovic; Woods, Amina S; Kiyatkin, Eugene A
In: Sci Rep, vol. 10, no. 1, pp. 833, 2020, ISSN: 2045-2322 (Electronic); 2045-2322 (Linking).
While it is known that opioid receptors (ORs) are densely expressed in both the brain and periphery, it is widely accepted that hypoxic effects of opioids result solely from their direct action in the CNS. To examine the role of peripheral ORs in triggering brain hypoxia, we used oxygen sensors in freely moving rats to examine how naloxone-HCl and naloxone-methiodide, the latter which is commonly believed to be peripherally restricted, affect brain oxygen responses induced by intravenous heroin at low, human-relevant doses. Similar to naloxone-HCl, naloxone-methiodide at a relatively low dose (2 mg/kg) fully blocked heroin-induced decreases in brain oxygen levels. As measured by mass spectrometry, naloxone-methiodide was found to be ~40-fold less permeable than naloxone-HCl across the blood-brain barrier, thus acting as a selective blocker of peripheral ORs. Despite this selectivity, a low but detectable amount of naloxone was found in brain tissue after naloxone-methiodide administration, potentially influencing our results. Therefore, we examined the effects of naloxone-methiodide at a very low dose (0.2 mg/kg; at which naloxone was undetectable in brain tissue) and found that this drug still powerfully attenuates heroin-induced brain oxygen responses. These data demonstrate the role of peripheral ORs in triggering heroin-induced respiratory depression and subsequent brain hypoxia.